Franzosa, J.A., Bugel, S.M., Tal, T.L., La Du, J.K., Tilton, S.C., Waters, K.M., and Tanguay, R.L. (2013) Retinoic acid-dependent regulation of miR-19 expression elicits vertebrate axis defects. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 27(12):4866-76.
Retinoic acid (RA) is involved in multifarious and complex functions necessary for vertebrate development. RA signaling is
reliant on strict enzymatic regulation of RA synthesis and metabolism. Improper spatiotemporal expression of RA during development
can result in vertebrate axis defects. microRNAs (miRNAs) are also pivotal in orchestrating developmental processes. While
mechanistic links between miRNAs and axial development are established, the role of miRNAs in regulating metabolic enzymes
responsible for RA abundance during axis formation has yet to be elucidated. Our results uncovered a role of miR-19 family
members in controlling RA metabolism through the regulation of CYP26A1 during vertebrate axis formation. Global miRNA expression
profiling showed that developmental RA exposure suppressed the expression of miR-19 family members during zebrafish somitogenesis.
A reporter assay confirmed that cyp26a1 is a bona fide target of miR-19 in vivo. Transient knockdown of miR-19 phenocopied axis defects caused by RA exposure. Exogenous miR-19 rescued the axis defects
induced by RA exposure. Taken together, these results indicate that the teratogenic effects of RA exposure result, in part,
from repression of miR-19 expression and subsequent misregulation of cyp26a1. This highlights a previously unidentified role of miR-19 in facilitating vertebrate axis development via regulation of RA signaling.